Impairments in memory function can range from the moderately inconvenient benign forgetfulness with normal aging to the devastating losses associated with Alzheimer's disease. In addition, alterations in the mechanisms that underlie normal memory are thought to underlie psychiatric disorders such as depression and post-traumatic stress disorder and may contribute to relapse in addiction. This grant uses animal models to identify the cellular and molecular mechanisms of memory formation. We use a genetic technique that allows us to introduce genes into specific parts of the brain and to turn them on or off at different times either during learning or during memory retrieval. For example, in one study we looked at a mouse model of a human genetic disorder (Rubenstein Taybi Syndrome) associated with both developmental abnormalities and severe cognitive impairment. One question that we addressed was whether the cognitive defects found in adults were due a defect in brain development or due to abnormal gene function in the adult brain. By inducing the genetic lesion only in the adult we could show that it produced learning and memory defects acutely and that these defects could be reversed by turning off the defective gene. We also showed that the behavioral defects could be reversed in this mouse model with a drug that targeted the biochemical defect. We apply this approach to a number of different cellular signaling pathways in neurons that are thought to underlie memory. We also use a genetic approach to analyze the anatomical structure of memory. Using this approach we hope to identify the individual neurons that contribute specific memories. We use this to address questions such as: Are the neurons activated during learning reactivated during recall? and Does the pattern of neuronal activation change as memories consolidate over time? By studying the specific cellular circuits that underlie memory we hope to more readily identify the underlying cellular and molecular mechanisms. PUBLIC HEALTH RELEVANCE This grant examines the mechanisms of learning and memory, from how brain cells are activated with learning to what genes and molecules in the cells are important for the formation of memories. We do these studies in mice because they are surprisingly similar to humans both genetically and in terms of brain structure. Memory is a basic element of brain function that is altered in many disease states from the degenerative diseases of aging like Alzheimer's to psychiatric disorders such as schizophrenia and post-traumatic stress disorder. One of the genes we work on is the mouse analogue of a gene that produces a form of mental retardation in humans.